Cytosine derivatives such as cytarabine, 1-(2′-cyano-2′-deoxy-β-D-arabinofuranosyl)cytosine, gemcitabine, decitabine, 5-azacitidine, RX-3117 (Rexahn), and SGI-110 (Astex), have effects of inhibiting cancer DNA polymerases or regulating the cancer cell cycle (G2/M arrest), and inducing differentiation of leukemic cells. Therefore, cytosine derivatives are useful as therapeutic agents for malignant tumors such as acute myelogenous leukemia, acute leukemia lymphocytic, malignant lymphoma, multiple myeloma, pancreatic cancer, lung cancer, and breast cancer (Patent Literature 1, Non-Patent Literatures 1 to 3). Therapy for malignant tumors using these cytosine derivatives involves administration of intravenous infusion that is usually sustained for several hours to several weeks (Non-Patent Literature 1).
Furthermore, mitomycin C is an anticancer agent used for the treatment of chronic lymphocytic leukemia, chronic myelogenous leukemia, gastric cancer, colorectal cancer, lung cancer, pancreatic cancer, liver cancer, cervical cancer, uterine cancer, head and neck tumor, and urinary bladder tumor. However, mitomycin C is also usually subjected to everyday intravenous administration. Gefitinib and erlotinib are molecular targeted anticancer agents that selectively inhibit tyrosine kinase of epithelial growth factor receptor (EGFR), and are used for, for example, non-small cell lung cancer, pancreatic cancer, glioblastosis cerebri, and head and neck squamous cell carcinoma. Furthermore, lapatinib and sunitinib are also tyrosine kinase inhibitors, and are used for, for example, breast cancer. However, these molecular targeted drugs also have a problem with adverse effects such as acute lung injury and interstitial pneumonitis.
Paclitaxel and docetaxel are anticancer agents used for the treatment of, for example, lung cancer, ovarian cancer, breast cancer, head and neck cancer, and progressive Kaposi's sarcoma. However, these taxane-based anticancer agents also have adverse effects such as myelosuppression such as leukopenia, and peripheral nerve disorder, and lack water-solubility. CREMOPHOR is obliged to be used as a dissolution aid, but since CREMOPHOR causes severe allergic symptoms, a pretreatment of histamine H1/H2 antagonists is indispensable, which requires complicated operations at administration in the clinical environment. Furthermore, there are occasions in which human serum albumin is used as a dissolution aid; however, there is a concern for risks such as lack of human serum albumin and viral infection such as AIDS.
Conventional anticancer agents formed from low molecular weight compounds have been clinically applied by intravenous administration or peroral administration; however, in the present circumstances they are still in low availability, and only an extremely small portion of the amount administered reaches tumors. In addition, the anticancer agents are systemically distributed, which leads to systemic toxicity. Since the dosage is determined by the balance between effect and toxicity, systemic toxicity occurs. Thus, in most cases, a sufficient amount of an anticancer agent required to exhibit the drug efficacy is not administered.
In recent years, several drug delivery systems have been developed for the purpose of overcoming the problems described above. For example, representative examples of drug delivery systems (hereinafter, referred to as DDS) include methods of physically embedding a low molecular weight anticancer agent in phospholipid liposomes, polymer micelles, or a water-soluble polymer, all of which are formed from biocompatible material components, or forming chemical covalent bonds between the two.
Regarding a liposome preparation for intravenous administration, since the particle size is controlled to be 200 to 300 nm so that liposomes can pass through capillary blood vessels without any problem and can pass through new blood vessels near a tumor, and in addition to that, since the membrane surface of the liposome particles is coated with a polyethylene glycol (hereinafter, referred to as PEG) having a molecular weight of about 2,000, ingestion of the liposomes by phagocytes in vivo is generally avoided.
In a polymer micelle preparation, since the particle size is controlled to 50 nm, and the membrane surface of the particles is coated with PEG, ingestion of the micelles by phagocytes in vivo can be generally avoided, and it has been reported that the polymer micelles can easily pass through new blood vessels near a tumor.
However, in the present circumstances, the above-mentioned preparations containing nano-sized fine particles have relatively short half-lives in blood, targeting to tumors is also unsatisfactory, and the intrinsic purpose is not sufficiently achieved.
Meanwhile, attempts have recently begun for clinical application of derivatives in which an anticancer agent is chemically covalently bonded to a synthetic high-molecular weight PEG having high biocompatibility and high water-solubility, particularly a PEG having four chains (molecular weight 40,000) that does not easily form a high viscosity solution.